JP2008529667A - Medical device - Google Patents

Abstract

で示されるセファロタキシンを宿主に投与しまたは送達するのに有用な医療デバイス、医薬組成物、および医療方法を提供する。本発明は、該セファロタキシンが血管新生の病気または疾患を治療しまたは予防するのに有用である、ことをも提供する。本発明は、血管新生の病気または疾患を処置するのに、マトリックスおよびセファロタキシンを含有するコーティングを含有する医療デバイスをも提供する。本発明は、抗血管新生薬としてのセファロタキシンアルカロイドを含有する、血管新生の病気もしくは疾患を有する宿主の治療のための、または血管新生の病気もしくは疾患の発症もしくは進行を阻害するための宿主の予防学的な処置のための、方法および組成物をも提供する。本発明はまた、セファロタキシンをインビボで送達しまたは投与するのに有用な医療デバイスをも提供する。The present invention has the formula:

The present invention provides medical devices, pharmaceutical compositions, and medical methods useful for administering or delivering a cephalotaxin represented by The present invention also provides that the cephalotaxin is useful for treating or preventing angiogenic diseases or disorders. The present invention also provides a medical device containing a matrix and a coating containing cephalotaxin to treat an angiogenic disease or disorder. The present invention relates to a host for treating a host having an angiogenic disease or disorder, or for inhibiting the onset or progression of an angiogenic disease or disorder, comprising a cephalotaxin alkaloid as an anti-angiogenic agent. Also provided are methods and compositions for prophylactic treatment. The present invention also provides medical devices useful for delivering or administering cephalotaxin in vivo.

Description

Related applications

  This application claims the benefit of US Provisional Application No. 60 / 651,757, filed February 10, 2005.

  The present invention provides medical devices, pharmaceutical compositions, and medical methods useful for administering or delivering cephalotaxin to a host.

  Angiogenesis is defined as the formation and differentiation of new blood vessels. As such, it is associated with numerous diseases and illnesses, particularly cancer, inflammation and certain retinal disorders. Angiogenesis inhibitors are recently high profile drugs in the fight against cancer. Some compounds, most notably angiostatin, endostatin, combretastatin, SU5416, TNP470, anti-VEGF compounds and others are proceeding to clinical trials as anticancer agents.

  Angiogenesis, which is the process by which new blood vessels are formed, is essential for normal body activity (including reproduction, development, wound repair). The process is not fully understood, but is thought to be involved in complex interactions of molecules that control the proliferation of endothelial cells (primary cells of capillaries). Under normal conditions, these molecules maintain the microvasculature in a quiescent state (ie, one without capillary growth) for an extended period of time (which can last several weeks, sometimes 10 years). Conceivable. If necessary (eg during wound healing), these same cells can undergo rapid growth and turnover within 5 days (by Folkman, J. and Shing, Y., J. Biol. Chem. , 267 (16), 10931-10934; and Folkman, J. and Klagsbrun, M., Science, 235, 442-447 (1987)).

  Angiogenesis is a highly controlled process under normal conditions, but many diseases (which are characteristic as angiogenic diseases or conditions) work by persistent uncontrolled angiogenesis . Otherwise, uncontrolled angiogenesis can cause certain diseases directly or exacerbate existing pathological illnesses. For example, ocular neovascularization has been linked as the most common cause of blindness and dominates about 20 eye diseases. In existing diseases (eg, arthritis), newly formed capillaries invade the joint and destroy cartilage. In the case of diabetes, new capillaries that form in the retina invade the vitreous, bleed, and cause blindness. Solid tumor growth and metastasis is also dependent on angiogenesis (Folkman, J., (1986) Cancer Research, 46, 467-473; Folkman, J., (1989) J. National Cancer Institute, 82, 4-6 (both of which form part of this specification). For example, tumors that expand to more than 2 mm have to obtain their own blood supply and this has been found to do so by causing new capillary growth. After these blood vessels are embedded in the tumor, they provide a means for the tumor to metastasize to different sites (eg, liver, lung, or bone) (Weidner, N. et al., (1991) The New England Journal of Medicine, 324 (1), 1-8).

  To date, several naturally occurring angiogenic factors have been described and confirmed (by Fidler, J. I. and Ellis, L. M., (1994) Cell, 79, 185-189). Recently, O'Reilly et al. Isolated and purified a 38 kilodalton (kDa) protein that inhibits endothelial cell proliferation from the serum and urine of tumor-bearing mice (O'Reilly, M. et al., ( 1994) Cell, 79, 315-328; and international patent application WO 95/29242 (published November 2, 1995)). Small sequence analysis of this endothelial inhibitor showed 98% sequence homology with an internal fragment of mouse plasminogen. Angiostatin (called the mouse inhibitory fragment) was a peptide containing the first 4 kringle region of mouse plasminogen. Peptide fragments derived from the same region of human plasminogen (ie, containing kringle 1-4) also strongly inhibited capillary endothelial cell proliferation in vitro and in vivo. Intact plasminogen from which this peptide fragment was derived had no strong inhibitory effect.

  Several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases (by Gasparini, G. and Harris, AL, (1995) J. Clin. Oncol., 13 (3 ): 765-782), there are disadvantages associated with these compounds. For example, suramin is a potent angiogenesis inhibitor, but at the doses required for antitumor activity, it causes severe systemic toxicity. For example, compounds such as retinoids, interferons, and antiestrogens are safe for human use but have a weak anti-angiogenic effect.

  Arterial narrowing and blood clotting are two related life-threatening diseases commonly associated with the circulatory system. Stenosis is a narrowing of blood vessels, usually due to fat and / or cholesterol accumulation. Thrombosis is the formation of blood clots inside the blood vessels or cavities of the heart. Both can cause vascular occlusion. Currently, the method for arteries that are clogged or constricted due to stenosis is balloon angioplasty or percutaneous coronary angioplasty (PTCA). However, about 30-40% of patients undergoing PTCA suffer from restenosis or restenosis of the blood vessels within 3-6 months of the method. Restenosis mainly results from the proliferation of vascular smooth muscle cells and the secretion of extracellular matrix at the site of injury. The patient may have to undergo subsequent angioplasty. Restenosis is a medical device, such as a stent, which can support the arteries and has recently spread by angioplasty to prevent elastic recoil of the arteries Can be suppressed by the use of Non-coronary vessels are also affected by restenosis. The carotid, femoral, iliac, and renal arteries may undergo restenosis after angioplasty and / or stenting procedures.

  Recent studies suggest that stent-based delivery of angiostatin, an angiogenesis inhibitor, can have a beneficial effect on patients after angioplasty and stent placement (by Ganaha F. et al., J. Vasc. Interv. Radiol. 2004 Jun; 15 (6): 601-8). In addition, multi-coated drug-eluting stents have been developed for antithrombotic and anti-restenosis treatment (Byun et al., US Pat. No. 6,702,850, and Yang et al., US Pat. No. 6,258,121) .

  Accordingly, there is a need for compounds that are useful in treating neovascular diseases or conditions in mammals. In addition, there is a need for compounds useful in the prophylactic treatment of hosts to prevent or inhibit the onset, progression or reoccurrence of angiogenic diseases or conditions. Moreover, there is a need for a medical device that can deliver an angiogenesis inhibitor to a patient having an angiogenic disease or condition and / or undergoing a medical method (eg, PTCA).

  Although several anti-angiogenic inhibitors have been identified, improvements in clinical use are still being explored. The invention described herein relates to medical devices or novel uses thereof of cephalotaxin alkaloids and their derivatives, including homoharringtonine, that can inhibit angiogenesis and consequently affect vascular diseases or conditions. Show.

(Summary of Invention)
The present invention relates to medical devices, pharmaceutical compositions, and medical methods useful for administering or delivering cephalotaxin to a host. The cephalotaxin is useful for treating or preventing angiogenic diseases or disorders. The present invention provides a medical device for treating an angiogenic disease or disorder comprising a matrix and a coating comprising cephalotaxin. The present invention relates to a method for treating a host having an angiogenic disease or disorder, or for inhibiting the onset or progression of an angiogenic disease or disorder, comprising a cephalotaxin alkaloid as an anti-angiogenic agent. Methods and compositions are provided for prophylactic treatment. The present invention also provides medical devices useful for delivering or administering cephalotaxin in vivo.

  In one embodiment, the medical device has a device body and a coating (matrix) on the surface of the device body, wherein the coating comprises cephalotaxin alone or in combination with another active drug. The devices include catheters, endoscopes, wound healing bandages, tissue / organ barriers, sutures, artificial organs, artificial organoids, implantable monitors, defibrillators, pacemakers, implantable pumps, cell reservoirs, prosthetic devices, and It can be a shaping device. In certain embodiments, the device is other than a stent.

  In another embodiment, the medical device is comprised of a stent and a coating (matrix) on the surface of the stent comprising cephalotaxin. In certain embodiments, the stent does not have another single heparin-containing coating. The coating of the device of the present invention may comprise a polymer (eg, a biopolymer or a synthetic polymer). Alternatively, the coating can include a non-polymeric material. The cephalotaxin contained in the coating includes homoharringtonine (cephalotaxin, 4-methyl-2-hydroxy-2- (4-hydroxy-4-methylpentyl) butanedioic acid ester) or a cephalotaxin analog. The medical device can include one or more coatings, and the coating can include a second drug. The medical device can also be a matrix containing cephalotaxin alone or in combination with other active drugs.

  The medical device is applicable for cardiology, ophthalmology, inflammatory disease, infection control, surgical adhesion control, intraoperative application method, wound healing management, burn dressing, medical imaging, and other application methods Can be used.

  The present invention also provides a method of contacting a host with a medical device in vivo. In certain embodiments, the device provides an amount of cephalotaxin sufficient to inhibit angiogenesis. In other embodiments, the cephalotaxin inhibits the development or progression of an angiogenic disease. The medical device is preferably implanted in the host. The present invention also provides a delivery device having a catheter having a cavity and a cephalotaxin-containing stent contained in the cavity.

(Detailed description)
The embodiments of the invention described herein are not intended to be exhaustive or to limit the invention to the embodiments specifically disclosed below. The disclosed embodiments are chosen so that others skilled in the art can appreciate and understand the principles and practices of the present invention.

  Provided are medical devices, medical methods, and pharmaceutical compositions for delivering or administering cephalotaxin to a host to treat a disease or condition. Cephalotaxin may be useful in (1) treatment of a host having an angiogenic disease; and (2) prophylactic treatment of the host to prevent the onset or progression of an angiogenic disease. In certain embodiments, cephalotaxin treats a disease or condition in a host by having an effect in the host (eg, including, but not limited to, inhibiting angiogenesis, inhibiting inflammation, and / or inhibiting cell proliferation). (Not limited).

  The medical devices, medical methods, and pharmaceutical compositions provided herein are used in a host or host treatment. “Host” includes both humans and other animals, particularly mammals. Thus, the method is applicable to both human therapy and veterinary uses. The host can be a patient. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment, the patient is a human.

  Compounds or chemical drugs (eg cephalotaxin) are known for their antiproliferative properties. Cephalotaxin is used herein as an inhibitor of angiogenesis (ie, an inhibitor of angiogenesis) in a preferred embodiment. Cephalotaxin is found in Cephalotaxus fortunei Hook and other related species (eg, Cepholotaxus sinensis Li, C. hainenensis, and C. wilsoniana (which includes C. oriliana). (Including by powell, RG, (1972) J. Pharm Sci., 61) from the skin, stems, leaves and seeds of beri mast and C. harringtonia) (8): 1227-1230).

  As used herein, the term “cephalotaxin” includes all elements of the chemical family, including alkaloid derivatives and analogs of the Chinese evergreen tree Inepaya (Cephalotaxus fortunei). The cephalotaxin family is defined by the chemical structure shown in FIG.

Cephalotaxin analogs are defined by the structure shown in FIG. 1 with substituents at R ₁ and R ₂ , but are not limited thereto. Examples of R ₁ and / or R ₂ include esters (e.g., harringtonine, iso Ha ring phosphatonin, homoharringtonine, deoxy Ha ring phosphatonin, and the like are formed acetyl cephalotaxine) a. Table 1 illustrates the structure of R ₁ and R ₂ for some of these analogs. R ₁ and R ₂ substituents are typically used to improve biological activity, pharmaceutical contributions (eg, bioavailability or stability), or to reduce toxicity. In one embodiment, R ₁ and / or R ₂ includes an alkyl substituent (eg, methyl, ethyl, propyl, etc.). In another embodiment, R ₁ and / or R ₂ comprises an ester (eg, methoxy, ethoxy, butoxy, etc.). In other embodiments, R ₁ and R ₂ are esters, such as — (O—C (O) —X), where X is alkyl or substituted alkyl.

  A specific example of cephalotaxin is homoharringtonine, which is a butanedioic acid ester of cephalotaxin, 4-methyl-2-hydroxy-2- (4-hydroxy-4-methylpentyl) (FIG. 2). .

  As illustrated in the examples, cephalotaxin is an angiogenesis inhibitor. One aspect of the present invention is to provide medical devices, medical methods, and pharmaceutical compositions for delivery or administration of cephalotaxin to a host. In each case, the cephalotaxin is provided in an amount sufficient to inhibit or prevent angiogenesis. In a preferred embodiment, the cephalotaxin is used because of its anti-angiogenic properties, i.e. to treat angiogenic diseases. In further embodiments, the present invention provides medical devices, medical methods, and pharmaceutical compositions for the delivery of cephalotaxin for use in prophylactic treatment to prevent the onset or progression of angiogenic diseases or conditions. Offer things.

  Inhibition of angiogenesis by cephalotaxin is useful for treating or preventing an angiogenic disease or condition. Examples of angiogenic diseases or conditions include, for example, diabetic retinopathy, inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, asthma, and pulmonary fibrosis), macular degeneration, angiofibroma, angiogenic glaucoma ( neovascular glaucoma), stenosis, thrombosis, restenosis, psoriasis, corneal graft angiogenesis, purulent granulomas, retrophakic fibroproliferation, scleroderma, granulation, hemangiomas, trachoma, hemophilic joint As well as vascular adhesion.

  In certain embodiments, the medical device is used to deliver cephalotaxin to solid tumors to inhibit angiogenesis. In this case, the function of the solid tumor is combined with an angiogenic disease. Tumor growth and metastasis depend on angiogenesis. Solid tumors require oxygen and nutrients to survive and grow. If no blood is supplied, the potential tumor either dies or remains dormant. These potential tumors can be, for example, microneoplastic or micrometastatic cancer cells. “Microtumors” remain as a stable cell population in which dying cells are replaced by new cells. A microtumor can be the start of a solid tumor, for example, in a host that has no other solid tumor. A microtumor can also be a residual tumor cell present in the host after the solid tumor from which the microtumor has metastasized has been removed or eradicated. This disease can occur in a host in which a cancerous tumor is in remission. The micrometastatic cancer cell means a cancer cell that has not yet been vascularized and forms a solid tumor.

  A microtumor becomes a fast proliferating tumor when vascularized, and it can expand to 16,000 times its original size two weeks after vascularization. In the absence of blood supply, no growth is seen (Folkman, J., (1974) Tumor Angiogenesis, Adv. Cancer Res. 19: 331 358; Ausprunk, DH and Folkman, J., (1977) Migration and Proliferation of Endothelial Cells in Preformed and Newly Formed Blood Vessels During Tumor Angiogenesis, Microvasc. Res. 14: 53-65 (both of which form part of this specification)).

  In addition to providing nutrients and oxygen to the tumor, angiogenesis allows solid tumors to metastasize. New blood vessels provide a pathway that allows cells to metastasize from a solid tumor to other sites in the host, resulting in secondary tumor formation.

  Thus, by suppressing angiogenesis, tumor and / or microtumor angiogenesis is minimized and the progression of metastasis and tumor growth is suppressed or stopped.

  In one embodiment of the invention, cephalotaxin is administered or delivered to a host having a microtumor. The cephalotaxin is administered or delivered in an amount sufficient to inhibit angiogenesis, thereby inhibiting the growth and metastasis of the microtumor. The microtumor can be an early onset of a disease characterized by tumor growth. The microtumor may be the result of established solid tumor metastasis.

  Another disease characterized by excessive blood vessel growth is diabetic retinopathy. Recent studies have shown a pathogenic role for the renin-angiotensin system (RAS) and vascular endothelial growth factor (VEGF) in the eye in response to chronic hyperglycemia (by Wilkinson-Berka JL et al., ( 2001) The Interaction Between the Renin-Angiotensin System and Vascular Endothelial Growth Factor in the Pathogenesis of Retinal Neovascularization in Diabetes, J. Vasc. Res., 38 (6): 527-35).

  In one embodiment of the invention, cephalotaxin is administered to a host suffering from or at risk of suffering from diabetic retinopathy. The cephalotaxin is administered or delivered in an amount sufficient to inhibit angiogenesis, thereby slowing the progression of diabetic retinopathy. In a preferred embodiment, a medical device comprising matrix particles containing cephalotaxin is administered intraoccularly for dispersion in or near the retina.

  Angiogenesis is involved in chronic inflammatory diseases, including rheumatoid arthritis, osteoarthritis, asthma, and pulmonary fibrosis (by Walsh, DA and Pearson 'CI, (2001), Angiogenesis in the Pathogenesis of Inflammatory Joint and Lung Diseases, Arthritis Res., (3): 147-153; Storegard1, CM et al., (1999), Decreased Angiogenesis and Arthritic Disease in Rabbits Treated with an vβ3 Antagonist, J. Clin. Invest, 3 (1): 47-54 (each of which forms part of this specification).

  In one embodiment of the invention, cephalotaxin is administered or delivered in an amount sufficient to inhibit angiogenesis to a host having an inflammatory disease, thereby slowing the progression of the inflammatory disease. In a preferred embodiment of the invention, the inflammatory disease is osteoarthritis. In each case of arthritis, a medical device containing a matrix containing cephalotaxin is injected into the bursa of the affected joint. In another embodiment, the inflammatory disease is asthma or pulmonary fibrosis.

  Cephalotaxin is administered or delivered to the host as a prophylactic treatment. “Prophylactic treatment” means administration or delivery of cephalotaxin to a host to prevent the onset or progression of a vascular disease. In this embodiment of the invention, cephalotaxin is administered or delivered to a host to prevent the development of tumor growth or metastasis, or a disease characterized by tumor growth or metastasis. The treatment may be desirable, for example, in a host that exhibits growth of a tumor (eg, a cancerous tumor) but is currently in remission.

  Cephalotaxin is administered or delivered to the host to prevent the onset or progression of angiogenic diseases other than the growth of cancerous tumors. In this embodiment, the cephalotaxin is administered or delivered to a host at risk of exhibiting an inflammatory disease (eg, rheumatoid arthritis, osteoarthritis, asthma, or pulmonary fibrosis).

  In a further preferred embodiment, cephalotaxin is administered or delivered to a host who is or is at risk of becoming diabetic as a prophylactic treatment to prevent or inhibit the development of diabetic retinopathy. In another more preferred embodiment, cephalotaxin is administered or delivered to a host (eg, an elderly person) at risk for developing macular degeneration as a prophylactic treatment to prevent or inhibit the development of macular degeneration. The

  For the prophylactic treatment described above, the cephalotaxin is administered or delivered in an amount sufficient to inhibit the onset or progression of an angiogenic disease.

  The medical device is (1) a device body coated with a matrix containing cephalotaxin alone or in combination with other active drugs, or (2) cephalotaxin alone or in combination with other active drugs. Containing matrix. The medical device can be delivered orally, intravenously, topically, intravascularly, intraperitoneally, intramuscularly or intradermally. The matrix can be a biodegradable polymer that allows for sustained release of cephalotaxin. Such biodegradable polymers are described in detail, for example, by Brem et al., J. Neurosurg. 74: 441-446 (1991), and elsewhere herein.

  The types of active agents or drugs other than cephalotaxin that can be used in the matrix of the medical device include antiproliferative drugs, cell division inhibitors, cytotoxic drugs, apoptosis inducers, signal transduction factors, kinases and phosphatases. Inhibitors and inducers, radiation sensitizers, radioprotectors, DNA repair inhibitors, antiviral drugs, antibacterial drugs, antifungal drugs, anthelmintic drugs, cancer chemotherapeutic drugs, anti-inflammatory drugs, compounds that affect lipid metabolism, glucose Compounds, neuroactive / neuroprotective drugs, drug resistance reversal drugs, chemical protective drugs, cytokines, growth factors, lymphokines, therapeutic antibodies, gene therapy RNAi / antisense therapeutics, and the like.

  In certain embodiments, the active drug suitable for use in the matrix is a compound of natural product origin, plant alkaloid, macrolide, terpene, antibiotic, vinca alkaloid, camptothecin, taxane, taxane analog, bruceantin ), Vancomycin and the like, but is not limited thereto. For example, the cephalotaxin described herein is active as an antiproliferative agent. As described herein, they also affect angiogenesis, induce apoptosis, and affect aspects of signal transduction pathways, which are novel and useful materials (eg, medical devices Or the matrix described herein is used alone or in combination with other drugs and / or excipients described herein to create therapeutic materials.

  In one embodiment, active drugs suitable for use in the matrix include, but are not limited to, the following anticancer drugs: Acivicin, aclarubicin, acodazole, aclonisin, adzelesin, alanosine, aldesleukin, allopurinol sodium, altretamine, aminoglutethimide, amonafide, ampligen, amsacrine, androgen, anguidine, aphidicolin glycine acid, asley ), Asparaginase, 5-azacytidine, azathioprine, bacilli Calmette Guerin (BCG), Baker's Antifol (soluble), beta-2'-deoxythioguanosine, bisanthrene hydrochloride (hcl), bleomycin sulfate, Busulfan, buthionine sulfoximine, BWA 773U82, BW 502U83. HCl, BW 7U85 mesylate, ceracemide, carbetimer, carboplatin, carmustine, chlorambucil, chloroquinoxaline-sulfonamide, chlorozotocin, chromomycin A3, cisplatin, cladribine, corticosteroid, corynebacterium Parbum, CPT-11, crisnatol, cyclocytidine, cyclophosphamide, cytarabine, cytembena, dabis maleate, dacarbazine, dactinomycin, daunorubicin HCl, deazauridine, dexrazoxane, Dianhydrogalactitol, diaziquone, dibromodulcitol, didemnin B, diethyldithiocarbamate, diglyco Rudehyde (diglycoaldehyde), dihydro-5-azacytidine, doxorubicin, echinomycin, edatrexate, edelfosine, edelfomycin, eflomithine, Elliott's solution, elsamitrucin, sorbicin Estramustine acid, estrogen, etanidazole, ethiofos, etoposide, fadrazole, fazarabine, fenretinide, filgrastim, finasteride, flavone acetate, floxuridine phosphate , 5-fluorouracil, fluozole.RTM., Flutamide, gallium nitrate, gemcitabine, goserelin acetate, hepsulfam, hexamethylene bisacetamide, homoharringtonine, sulfur Hydrazine, 4-hydroxyandrostenedione, hydroxyurea, idarubicin HCl, ifosfamide, interferon alpha, interferon beta, interferon gamma, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin- 6,4-ipomeanol, iproplatin, isotretinoin, leucovorin calcium, leuprolide, levamisole, daunorubicin liposome, liposome-encapsulated doxorubicin, lomustine, lonidamine, maytansine, mechlorethamine hydrochloride, melphalan, menogalyl, merbarone 6-Mercaptopurine, Messna, Methanol extract residue of Bacillus Calmette Guerin, methotrexa , N-methylformamide, mifepristone, mitoguazone, mitomycin-C, mitotane, mitoxantrone hydrochloride, monocyte / macrophage colony stimulating factor, nabilone, nafoxidine, neocalcinostatin, octreotide acetate, ormaplatin, oxaliplatin, paclitaxel , Pala, pentostatin, piperazinedione, piperoman, pirarubicin, pyrtrexime, pyroxantrone hydrochloride, PIXY-321, pricamycin, porfimer sodium, prednisomine, procarbazine, progestin, pyrazofurin, razoxane, sargramostim, semustine , Spirogermanium, spiromustine, streptonigrin, streptozocin, slofenal, suramin sodium, Moxifen, taxotere, tegafur, teniposide, terephthalamidine, teroxirone, thioguanine, thiotepa, thymidine injection, thiazofurin, topotecan, toremifene, tretinoin, trifloperazine hydrochloride, trifluridine, trimethrexate, tumor necrosis factor, uracil Mustard, vinblastine sulfate, vincristine sulfate, vindesine, vinorelbine, vinzolidine, Yoshi 864, zorubicin, and mixtures thereof.

  In another embodiment, the active drug is an anti-inflammatory drug, which can include, but is not limited to, for example: Non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmethine, ketorolac, oxaprosin, mefenamic acid, fenoprofen , Nabumetone (relafen), acetaminophen (tylenol. RTM.), And mixtures thereof; COX-2 inhibitors such as nimesulide, NS-398, flosulid, L-745337, celecoxib, Rofecoxib, SC-57666, DuP-697, parecoxib sodium, JTE-522, valdecoxib, SC-58125, etoroxib, RS-57067, L-74878 , L-761066, APHS, etodolac, meloxicam, S-2474, and mixtures thereof; glucocorticoids (eg, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, triamcinolone, parameterzone, fluprednisolone, fluprednisolone, befluprednisolone, Dexamethasone, fludrocortisone, desoxycorticosterone, and mixtures thereof; and mixtures thereof.

  In one embodiment, the active drug can be a medical diagnostic imaging drug, such as, for example, paramagnetic materials (eg, nanoparticulate iron oxide, Gd or Mn), radioisotopes, and non-toxic radiopaque ( radio-opaque) markers (eg, but not limited to barium sulfate cages and bismuth trioxide). A radiopacifier (eg, radiopacifier) can be included in any manufacturing method, or adsorbed onto or on the surface of some or all of the medical devices described herein. Can be sprayed on. A contrast agent (eg, radiopaque material) can be included in any manufacturing method, or can be adsorbed or sprayed onto some or all of the surface of the medical device of the present invention. The size of the radiopaque contrast can be varied by controlling the concentration of the contrast agent in or on the implant. Radiopacity can be imparted by covalently binding iodine to the polymer monomer building blocks of the implant elements. Common radiopaque materials include barium sulfate, bismuth subcarbonate, and zircon dioxide. Other radiopac materials include cadmium, tungsten, gold, tantalum, bismuth, platinum, iridium, and rhodium. In certain embodiments, iodine can be used for both its radiopaque and antibacterial properties. This is useful for detection of the medical devices described herein that are implanted in the body (embedded at the treatment site) or move parts of the body (ie during the implant of the device). Can be useful. Paramagnetic resonance imaging, ultrasound imaging, x-ray methods, fluoroscopy, or other suitable detection techniques can detect medical devices containing these materials. In certain embodiments, the medical diagnostic imaging drug can assist medical diagnostic imaging of the medical devices described herein once implanted.

  In another embodiment, the active drug can be an immunosuppressant, including, but not limited to, cyclosporine, tacrolimus FK506, rapamycin (sirolimus), and rapamycin analogs. Rapamycin analogs include, but are not limited to, for example, CCI-779 (Wyeth), RAD001 or Everolimus (Novartis), and AP23573 (Allied Pharmaceuticals). Rapamycin can be used to prevent kidney transplant rejection. It itself has also been reported to be effective in preventing restenosis (Serruys, P. E. et al., Heart 2002, 87; 305-307). In one embodiment, the matrix comprises cephalotaxin and rapamycin, or one of its analogs. In another embodiment, the matrix comprises cephalotaxin, rapamycin, or one of its analogs, and another active drug.

  In another embodiment, the active drug can be a promoter of wound healing, including but not limited to granulocyte macrophage colony stimulating factor (GM-CSF) and / or growth factor.

  In another embodiment, the matrix containing the first active drug and the second active drug is directly or such that the amount of the first active drug delivered modulates a disease or disorder in the host. The matrix-coated medical device body is delivered to the host. The amount of the first active drug delivered can be such that the adjustment achieved is greater than if the host receives the second active drug without the first active drug. In a preferred embodiment, the first active drug is cephalotaxin. In a preferred embodiment, the medical device is a stent. In another preferred embodiment, the condition to be adjusted is restenosis. In a more preferred embodiment, the adjustment is inhibition of restenosis.

  The active agent or drug may be a natural or synthetic source, radionuclide, or biological product (eg, therapeutic peptide / protein, nucleic acid polymer (eg, DNA), mammalian or non-mammalian sequence (eg, plasmid or Viruses), synthetic nucleic acid polymers (eg, antisense nucleic acids, RNA interference)), which can be included alone or in combination to produce an appropriate biological / disease management effect be able to. The active drug contained in the biologically acceptable matrix may or may not be bound to the matrix. Bonds can be created until complexation or encapsulation by covalent, ionic, or hydrogen bonds. The resized particles of the active drug that can be used include nanoparticles, microparticles, emulsions with and without surfactants and stabilizers. In addition, other drugs and excipients can be used to provide sustained release, increased stability, antioxidant properties, and the like.

  Devices that can use these matrices include, for example, catheters (balloon catheters or dilatation catheters, injection catheters, central venous catheters and arterial catheters), and stents (vascular stents, urethral stents, biliary stents, bile stents, esophagus) Stents, trachea or bronchial stents), vascular stent grafts, endoscopes, wound healing dressings, tissue barriers or organ barriers (eg surgical adhesion prevention), sutures, artificial organs or organoorganoids (eg insulin secretion devices) Implantable monitors, defibrillators, ventricular assist devices), pacemakers, implantable pumps, cell reservoirs (eg for stem cell placement), prosthetic devices (prosthesis) Including heart valves), but may include shaping devices, and the like. Other devices include surgical clasps, guide wires, cannulas, cardiac pacemakers, and electrical stimulation leads or lead tips, defibrillator leads or lead tips, implantable vascular access ports, blood storage bags, blood tubes, blood vessels or Other grafts, intra-aortic balloon pumps, heart valves, cardiovascular sutures, total heart and ventricular assist pumps, and extracorporeal devices such as blood oxygenators, blood filters, septal defect devices, hemodialysis units, blood Perfusion unit, plasmapheresis unit, anastomosis device, implantable biosensor, implantable drug infusion tube, birth control occlusion device, breast implant, pain management device, prostate cancer treatment device, dental implant, focal epilepsy treatment device Nerve regeneration conduit, vena cava filter, spinal cord repair device, spinal cord stimulator, internal hearing aids, neuroaneurysm treatment device, heart valve repair device, intravitreal drug delivery device, joint replacement, ophthalmic implant , Needles, and vascular grafts.

  Suitable medical devices for the present invention include devices having tubular or cylindrical portions. In another embodiment, the device is in the form of a disk. The disc may be composed of stainless steel or another biocompatible material as described herein. The tubular portion of the medical device need not be completely cylindrical. For example, the cross-section of the tubular portion can be any shape (eg, square, triangle, etc .; but not exactly circular). Such devices include, but are not limited to, stents, balloon catheters, and grafts. Bifurcated stents are also included in the medical device that can be manufactured according to the present invention. Medical devices particularly suitable for the present invention include any type of stent for medical purposes known to those skilled in the art.

  The device of the present invention may be constructed in part or in whole from a biocompatible material, which typically has the ability to support tissue. In one embodiment, the tissue is a blood vessel, preferably a deficient blood vessel. In one embodiment, the material is a biocompatible metallic material. The metallic material can be a metal or an alloy. Types of metallic materials include titanium, nitinol, nickel titanium alloys, thermal memory alloy materials, stainless steel, tantalum, nickel-chromium, gold and certain cobalt alloys (eg, cobalt-chromium-nickel alloys). However, it is not limited to these.

  In another embodiment, the biocompatible material is plastic, ceramic, or another suitable material. Ceramic materials may include, for example, transition element oxides, carbides, or nitrides (eg, titanium oxide, hafnium oxide, iridinium oxide, chromium oxide, aluminum oxide, and zircon oxide), It is not limited to these. Silicon-based materials (eg, silica) can also be used.

  In one embodiment, the present invention provides a medical device suitable for in vivo use in a patient. The use can include implanting a patient. The medical device may be partially or entirely composed of a biodegradable material or a bioabsorbable material. In another embodiment, the medical device is an implantable intraluminal device. Biologically active substances can be delivered to the body lumen using the medical devices described herein. For example, a stent can be inserted into a patient's body by methods known to those skilled in the art. If the stent is a self-expanding stent, it collapses to a small diameter by placing it in the outer tube, is introduced into the lumen of the patient's body using a catheter, and is removed from the outer tube It can be expanded into the target area by removing. If the stent is a balloon expandable stent, it can collapse to a small diameter, be placed on the angioplasty balloon catheter, and moved into the area to be installed. When the balloon is inflated, the stent expands.

  The device (eg, stent) of the present invention is coupled with a vascular graft in an expandable lumen to dilate a partially occluded segment of a blood vessel, vessel, body passage, or vessel (eg, in an organ). Can be used. In addition, the device can also be used for many other purposes as a scalable prosthesis for many other types of body passageways. For example, scalable prosthesis can also be used for the following purposes: (1) Placement of supportive grafts in blocked arteries opened by transluminal recanalization with the ability to collapse without internal support; (2) Mediastinal and other obstructions due to inoperable cancer Similar use after passage through a catheter through a vein of the vein; (3) Enhanced intrahepatic information exchange of catheter creation between the portal vein and hepatic vein in patients with portal hypertension; (4) Esophageal, intestine (5) Intraluminal bypass of defects (eg, aneurysms or obstructions) in blood vessels and organs; (6) Reopening and earlier Placement of a supportive graft of obstructed bile ducts. Thus, the use of the term “prosthesis” encompasses the above uses in various types of intracorporeal passages, and the use of the term “intraluminal graft” or “intraluminal medical device” Includes use to extend and / or maintain patency of the cavity. Furthermore, the term “body passageway” includes any lumen or cavity in the body (eg, those described above), as well as any vein, artery, or blood vessel within the vasculature.

  Other vascular applications include anastomosis devices, occlusive devices (for the treatment of diseases such as vascular aneurysms or obstructions). Other exemplary applications include the treatment of septal defects and septal closure devices.

  Other non-vascular applications include neurology (brain), gastrointestinal tract, duodenum, bile duct, gallbladder duct, hepatic duct, esophagus, urethra, lymphatics, genital system, prostate, trachea, and respiratory tract (eg bronchi) Includes tube and otological applications.

  Other uses include shunts for various applications (eg hydrocephalus, cerebrospinal fluid shunt, urological application, glaucoma drain shunt); ear / nose / pharynx (eg ear drainage tube); kidney Devices; and dialysis (eg, grafts), nerve regeneration conduits, abdominal aortic aneurysm grafts, vascular interventional devices, urinary dilators, circulatory support systems, angiographic catheters, transition sheaths and dilators, tympanic incisions Includes a surgical decompression tube.

  The medical device of the present invention (which contacts an aqueous system (eg, body fluid)) can be used. The device is adapted to release a bioactive drug over a long period of time and in a controlled manner, usually starting with an initial contact between the device surface and its aqueous environment. Local delivery of a combination of bioactive drugs should be used to treat a wide range of diseases using any number of medical devices or to increase the function and / or lifetime of the device Can do. In essence, any type of medical device can be manufactured in several ways with one or more bioactive drugs that augment treatment beyond the use of the device or bioactive drug.

  The device of the present invention can be used to treat any implant site in the body, preferably providing a device that fully or partially degrades during use. In certain embodiments, the device is used to treat an implant site in the body. Here, it is preferred to allow and maintain the function of the implant site while restoring and maintaining the patency or integrity of the implant site. For example, in vascular applications, the device can repair and maintain the patency of the blood vessel site treated with the device, so that constant blood flow flows through the treatment site. It becomes possible. In certain embodiments, the devices of the present invention further provide sustained release of one or more bioactive drugs.

  The devices described herein are formed by a variety of methods known to those skilled in the art including, but not limited to, microfibers or fiber welding, molding, and winding or braiding. Thus, a continuous structure can be formed.

  In one embodiment, the active agents of the present invention are provided by the medical devices described herein. In a preferred embodiment, some or all of the device is coated with a matrix, where the matrix is a polymer as described herein. In a more preferred embodiment, the matrix comprises the drug or active drug. In the most preferred embodiment, the active drug or drug is cephalotaxin.

Matrixes that can be used in drug or active drug use include polymers. Such polymers include, but are not limited to, biopolymers (eg, collagen, fibrinogen, hyaluronic acid, lipid complexes, chitin, albumin cyclodextrin, glucosamine, carbohydrate complexes, polylactide, polyglycolide, and copolymers thereof. Not). Such polymers include synthetic polymers such as Dacron, Nylon, Polyurethane, Lycra ^(R) , Gore-Tex ^(R) , polyethylene, polystyrene, polypropylene, polycarbonate, polyethylene glycol, and copolymers thereof. (But not limited to). Other suitable polymers include, but are not limited to, for example: Poly (L-lactide) (PLLA), poly (D, L-lactide) (PLA), polyglycolide (PGA), poly (L-lactide-co-D, L-lactide) (PLLA / PLA), poly (L L-lactide-co-glycolide) (PLLA / PGA), poly (D, L-lactide-co-glycolide) (PLA / PGA), poly (glycolide-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polycaprolactone (PCL), polyhydroxybutyrate (PHBT), poly (phosphazene), poly (D, L-lactide-co-caprolactone) (PLA / PCL), poly (Glycolide-co-caprolactone) (PGA / PCL), polyanhydride (PAN), poly (orthoester), poly (phosphate ester) Poly (amino acid), poly (hydroxybutyrate), polyacrylate, polyacrylamide, poly (hydroxyethyl methacrylate), elastin polypeptide copolymer, polyurethane, polysiloxane, ethylene vinyl acetate, polyethylene terephthalate, thermoplastic elastomer, polyvinyl Chloride, polyolefin, cellulose, polyamide, polyester, polysulfone, polytetrafluoroethylene, acrylonitrile butadiene styrene copolymer, acrylic, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymer, cellulose, polymethyl methacrylate , Polyalkylene oxalic acid, poly (dimethylsiloxane), polycyanoacrylate, polyphosphazene, ethylene glycol I Dimethacrylate, poly (methyl methacrylate), poly (2-hydroxyethyl methacrylate), polytetrafluoroethylene poly (HEMA), polyhydroxyalkanolate, poly (glycoside-lactide) copolymer, poly (γ-caprolactone), poly (γ-hydroxybutyrate), polydioxanone, poly (γ-ethylglutamate), polyiminocarbonate, poly (orthoester), polyanhydride, alginate, dextran, cotton, and copolymers or derivatives thereof, For example, a polymer modified to contain a binding position or a bridging group, where the polymer retains structural integrity while allowing binding to cells and molecules (eg, proteins, nucleic acids, etc.) is there).

The matrix that can be used in the active drug or drug use can comprise a non-polymeric matrix. Examples of non-polymeric materials include, but are not limited to: Sterols (eg, cholesterol, stigmasterol, β-sitosterol, and estradiol); cholesteryl esters (eg, cholesteryl stearic acid); C ₁₂ -C ₂₄ fatty acids (eg, lauric acid, myristic acid, palmitic acid, stearic acid, arachidone) acid, behenic acid, and lignoceric acid); mono C ₁₈ -C ₃₆ -, di -, and tri - acylglycerides (e.g., glyceryl oleate, glyceryl linoleate, glyceryl monolaurate acid acid, glyceryl docosanoic acid (docosanoate), glyceryl monomyristic acid, glyceryl monodisenoic acid, glyceryl dipalmitic acid, glyceryl didocosanoic acid, glyceryl dimyristic acid, glyceryl didecenoic acid (didecenoate), glyceryl tridoco Acids, glyceryl trimyric acid, glyceryl tridecenoic acid, glycerol tristearic acid, and mixtures thereof; sucrose fatty acid esters (eg, sucrose distearic acid and sucrose palmitic acid); sorbitan fatty acid esters (eg, sorbitan monostearic acid, sorbitan) monopalmitate and sorbitan tristearate,); C ₁₆ -C ₁₈ fatty alcohols (e.g., cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol); esters of aliphatic alcohols and fatty acids (e.g., Sechiruparumichin acid And cetearyl palmitic acid); fatty acid anhydrides (stearic anhydride); phospholipids (eg, phosphatidylcholine (lecithin), phosphatidyl) Including serine, phosphatidylethanolamine, phosphatidylinositol, and their soluble derivatives; sphingosine and its derivatives; sphingomyelin (eg, stearyl, palmitoyl, and tricosanyl sphingomyelin); ceramide (eg, Stearyl and palmitoyl ceramides); glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures thereof). Preferred non-polymeric materials include cholesterol, glyceryl monostearate, glycerol tristearate, stearic acid, stearic anhydride, glyceryl monooleic acid, glyceryl monolinoleic acid, and acetylated monoglycerides.

  The present invention provides a medical device having a coating that can be composed of a matrix containing one or more polymers. The coating can also include a matrix containing one or more non-polymeric materials. In addition, a matrix containing either a polymeric or non-polymeric material can also have one or more active drugs as described herein. In one embodiment, the medical device can have one or more coatings. In another embodiment, the coating substantially covers the complete surface of the device. In one embodiment, the coating covers a portion of the device. In addition, any portion of the device that has contact with an organic liquid may be coated as well. In a preferred embodiment, at least one surface of the medical device is coated with one or more polymers described herein. A coated device having a surface coated with the polymer may provide localized treatment at the implant site. The coating may be applied to the device prior to insertion into a patient using methods well known in the art (eg, including but not limited to solvent evaporation methods or controlled vacuum ultrasonic spray deposition processes). Applies to The coating method involves mixing one or more polymers described herein with an active drug and solvent described herein, and dipping or spraying the mixture onto the surface of a medical device. Applying and drying the medical device to evaporate the solvent and polymer. The surface of the medical device then includes a thin film containing the active drug. The drying step can also include evaporating only the solvent leaving a layer of active drug and polymer.

  In one embodiment, the first coating is applied to the medical device. The first coating can cover some or all of the device. In another embodiment, the second coating is then applied to the medical device. The second coating can cover a first region of the device not previously covered by the first coating. Alternatively, the second coating can cover a second region of the device previously covered by the first coating. In another embodiment, the second coating can cover the first region and the second region. In the most preferred embodiment, the second coating does not contain heparin. In addition, the present invention provides for the application of two or more coatings to the medical devices described herein.

  In another embodiment, the coating comprises a polymer and one or more drugs described herein. Release of the stored drug can be achieved by diffusion through the polymer-liquid surface and then into the liquid. Release can also occur by degradation of the polymer by hydrolysis, which erodes the polymer-compound layer and thus releases both into the liquid.

  Each coating may be provided on the surface of the device described herein in a series of applications. The number of applications can be selected to provide an appropriate thickness of the individual coating layers, as well as the desired total number of coatings, as desired. In the embodiment, the coating may be the same or different as desired. In other embodiments, the number of applications can be controlled to provide the desired total thickness to the polymer coating. Generally, the thickness of the coating is selected such that it does not significantly increase the profile of the device for implantation and use within the patient. The total thickness of the coating described herein can be from about 1 μm to about 100 μm.

  In one embodiment, the coating on the device is composed of multiple layers of degradable polymer material, each individual layer or layer classification may comprise a different active drug. For example, in a coronary stent, the coating can include an antithrombogenic agent (eg, heparin, coumadin, etc.) to reduce acute thrombosis. The coating may also include an antiproliferative agent (eg, cephalotaxin, everolimus, sirolimus, angiopeptin, paclitaxel, etc.) to prevent subacute restenosis. The coating may contain anti-inflammatory drugs (eg, cephalotaxin, aspirin, lipid-lowering statins, fat-lowering lipostavir, estrogen and progestins, endothelin receptor antagonists, interleukin-6 antagonists, monoclonal antibodies to VCAM or ICAM, etc. ).

  In one embodiment, the medical device of the present invention may be used in the field of cardiovascular medicine. Coronary angioplasty is a medical method used to repair blood flow through narrowed or blocked arteries in the heart. The arteries of the heart (coronary arteries) can be narrowed and blocked due to the accumulation of substances called plaques on their inner walls. This narrowing can reduce blood flow through the artery and, over time, can cause coronary heart disease and stroke. In angioplasty, a thin tube with a balloon or other device on the end can be passed first through the blood vessels in the arm or groin (upper thigh) to the site of narrowing or blocking in the coronary arteries. it can. Once placed, the balloon can then be inflated to push the plaque outwardly against the wall of the artery, thereby expanding the artery and repairing blood flow through it. . Angioplasty can be used to reduce chest pain caused by reduced blood flow to the heart and / or minimize damage to the myocardium during a heart attack.

  In the most preferred embodiment, the medical device is a stent. Stenosis means stenosis or narrowing. A narrowed or narrowed coronary artery is called stenosis. Accumulation of fat, cholesterol, and other substances over time can clog arteries. One method for dilating the coronary artery is by using PTCA (balloon angioplasty). Patients undergoing PTCA have the expanded segment restenosis (restenosis) within about 6 months of the method. The restenated artery may have to undergo another angioplasty procedure. One way to help prevent restenosis is by using a stent. Stents are tubes that can be composed of metal or plastic and can have either solid walls or mesh walls. The stent can be balloon expandable or self-expanding. They can be used to help open the artery after angioplasty.

  Stents can be thin mesh tubes that resemble small springs and are used in more recently developed angioplasty methods. The stent may include a mesh body that contains a series of openings. The stent of the present invention can be a coronary stent or a non-coronary stent. The stent can be inserted into a narrowed area to keep blood vessels (eg, arteries) open. The stent can be coated with drug therapy to help prevent the vessel from closing again. Stents can be used in most angioplasty procedures, where the blood vessels are large enough to accommodate the stent. In one embodiment, the stent can be used after an angioplasty method to inhibit restenosis by holding the affected blood vessel open.

  Vascular restenosis or restenosis after angioplasty procedures is not common in stented arteries. Research methods using stents covered with drugs that show promise to improve the long-term success of this method are ongoing. Stenosis can also occur after coronary artery bypass graft (CABG) surgery. This type of cardiac surgery is performed to re-route or “bypass” blood around a clogged artery. It also improves blood and oxygen supply to the heart. In this case, the stenosis can occur in the transplanted vascular segment. Like other constricted arteries, they may require angioplasty or atherectomy to reopen them.

  In one embodiment, the device of the present invention comprises a restenosis-inhibiting drug. In a preferred embodiment, the device is a stent. Restenosis-inhibiting drugs can include microtubule stabilizers (eg, taxol, paclitaxel, analogs, derivatives, and mixtures thereof). For example, suitable derivatives include 2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol, 2′-glutaryl-taxol triethanolamine salt, N- (dimethylaminoethyl) 2'-O-ester with glutamine and 2'-O-ester with N- (dimethylaminoethyl) glutamide hydrochloride. In addition, the restenosis-inhibiting drug can be cephalotaxin, and analogs, derivatives, and mixtures thereof. The inhibitory drug can be dissolved or dispersed in the polymeric material and the polymeric material can adhere to the stent body. In other embodiments, the matrix described herein can be sprayed, dipped or extruded onto the stent.

  In one embodiment, the coating described herein is substantially continuous on the stent body. In another embodiment, the coating is present primarily on the stent structure, but not on the opening. For example, in the case of a stent formed of a wire mesh, the coating can adhere tightly to the wire without covering the opening therebetween.

  The stent according to the present invention can be selected according to the desired release dose profile and delivered to the treating physician. After the method of angioplasty, a coated stent with an active drug that inhibits restenosis can be delivered to stenosis, which is now a dilated coronary artery region. Delivery can be accomplished using methods well known to those skilled in the art (eg, mounting a stent on an inflatable balloon that is disposed on the distal end of the catheter). When the stent is advanced to a position near the expanding region, the stent can be forced to a position relative to the outside and the interior of the vessel wall. If the stent is self-expanding, the stent can be delivered by placing the stent in a delivery device, thereby allowing the stent to expand relative to the vessel wall interior. Become. When released from an erodible polymer coating, the active agent or drug can be absorbed by the interior of the vessel wall. Over time, the polymer coating can be eroded by body fluids.

  In one embodiment, the medical device described herein is a drug-delivery device. In a preferred embodiment, the device has at least one surface containing a coating comprising a polymer described herein and a compound of the invention.

  In another embodiment, the medical device is a catheter.

  The dose of the compound will depend on the disease being treated, the compound, and other clinical factors (eg, the weight and condition of the human or animal and the route of administration or delivery of the compound). It should be understood that the present invention has application for use in both humans and livestock.

In one embodiment of the present invention, the cephalotaxine is administered or delivered to a host in the range of range from 0.05 to 5.0 mg / ^{m 2.} In a preferred embodiment, the cephalotaxine is administered or delivered to a host in the range of 0.1-3.0 mg / ^{m 2.} In a further preferred embodiment, the cephalotaxine is administered or delivered to a host in the range of 0.1 to 1.0 mg / ^{m 2.}

  The cephalotaxin is administered or delivered biweekly, weekly, daily, twice daily, or more as needed to inhibit angiogenesis or inhibit the development or progression of angiogenic disease can do.

  The medical device can be oral, intestine, eye (eg, including intravitreal or intraocular), nasal, topical (eg, buccal and sublingual), vaginal, or parenteral (eg, subcutaneous, intramuscular). , Intravenous, intradermal, intratracheal, and epidural) administration or delivery. The medical device can be easily provided in a single dosage form and can be manufactured by conventional pharmaceutical techniques. Such techniques include the step of combining a medical device and a pharmaceutical carrier or excipient. In general, the formulations are obtained by uniformly and intimately combining a matrix containing cephalotaxin with a liquid carrier or finely divided solid carrier or both and then, if necessary, molding the product. To manufacture.

  Formulations of the present invention suitable for oral administration or delivery usually contain a cephalotaxin containing matrix (wherein the cephalotaxin containing matrix each contains a predetermined amount of active ingredient, capsule, sachet, or These are powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water emulsions or water-in-oil emulsions, boluses, and the like.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. A compressed tablet is a cephalotaxin-containing matrix (which optionally comprises a binder, lubricant, inert diluent, preservative, surfactant, Or mixed with a dispersing agent). Molded tablets can be made by molding in a suitable machine a mixture of the powdered matrix moistened with an inert liquid diluent. The tablets can optionally be coated or scored and formulated to provide slow or sustained release of the matrix in the tablet over a period of minutes to hours, days.

  Formulations suitable for topical administration or delivery in the oral cavity include lozenges containing a cephalotaxin-containing matrix in a fragrance base (usually sucrose and acacia or tragacanth); an inert base (eg, Pastilles containing active ingredients in gelatin and glycerin or sucrose and acacia).

  Formulations suitable for topical administration or delivery to the skin may be provided as ointments, creams, gels, and pastes containing a cephalotaxin-containing matrix that is administered or delivered in a pharmaceutically acceptable carrier. it can. A preferred topical delivery system is a transdermal patch containing a medical device (matrix) to be administered or delivered.

  Formulations for enteral administration or delivery can be presented as suppositories with suitable bases containing, for example, cocoa butter or salicylic acid.

  Suitable formulations for nasal administration or delivery of a cephalotaxin-containing matrix, where the carrier is a matrix or a solid containing the matrix, are administered or delivered in a manner that administers or delivers a blowing agent (ie, near the nose). Including a coarse powder having a particle size in the range of 20 to 500 microns, for example, by fast inhalation through the nasal passage from a container of powder held in the container. For example, suitable formulations in which the carrier is a liquid for administration or delivery as a nasal spray or nasal spray include an active matrix or a solid aqueous or oily solution containing the matrix.

  Formulations suitable for vaginal administration or delivery, in addition to the medical device, contain carriers known to be suitable in the art, pessaries, tamports, creams, gels, pastes, foams, Or it can serve as a spray formulation.

  Formulations suitable for parenteral administration or delivery include aqueous and non-aqueous sterile injection solutions (including antioxidants, buffering agents, bacteriostatic agents, and isotonic with the blood of the intended recipient). As well as aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents. The formulation can be provided in single-dose or multi-dose containers, such as sealed ampoules and vials, and only requires the addition of a sterile liquid carrier (eg, water for injection) just prior to use. It can be stored under freeze-drying (freeze-drying) conditions. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

  Preferred single dose formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, as listed herein above, of the active ingredient to be administered or delivered. .

  In addition to the components (especially those described above), the formulations of the present invention can include other agents that are common in the art for the type of formulation of interest, eg, formulations suitable for oral administration or delivery It should be understood that may contain fragrances.

In addition, the cephalotaxin compositions of the present invention can be administered or delivered with other active compounds. Examples of active compounds that can be co-administered or co-delivered with the cephalotaxin composition include, for example, other anti-angiogenic agents (eg, angiostatin, VEGF inhibitor, endostatin, combretastatin, 2-methoxy-estradiol, thalidomide and Abasutachin (Avastatin) ^{(registered trademark),} taxanes, antimetabolites (e.g., methotrexate, corticosteroids, colchicine, and analogs), antibodies against angiogenesis targets, interferons, diabetes control agents (e.g., insulin, and insulin growth Factor inhibitors), anti-inflammatory agents (eg, COX-2 inhibitors), anti-arthritic agents, aspirin, ibuprofen, naprosin, etc .; gene therapy, antisense therapy, and RNA interference therapy against gene targets , Associated mRNA, and protein targets for angiogenesis, antisense therapy, and RNA interference therapy.

  The active ingredient can be administered or delivered to the host prior to, during, or after administration of the cephalotaxin composition. In one embodiment of the invention, the active ingredient is mixed with cephalotaxin prior to administration, and the mixture is administered or delivered to a host. In a further embodiment, the active ingredient and cephalotaxin are administered or delivered separately to the host but simultaneously. In another further embodiment, the active ingredient is administered or delivered prior to cephalotaxin. In a preferred embodiment, the active ingredient is administered or delivered prior to the cephalotaxin, with the active ingredient still systemically present in the host. In another further embodiment, the active ingredient is administered or delivered after cephalotaxin. In a preferred embodiment, the active ingredient is administered or delivered after cephalotaxin while the cephalotaxin is still systemically present in the host.

  Suitable hosts of the present invention include humans or other animals.

  The following examples are used to more fully describe the manner of using the present invention described above, as well as to describe the best mode contemplated for carrying out the various aspects of the present invention. It should be understood that these examples are not used in any way to limit the true scope of the invention, but rather are presented for illustrative purposes. All publications cited in this specification are part of this specification.

Example 1
Effect of homoharringtonine in CAM assay (protocol)
Chicken fertilized eggs (HiChick Breeding Co, Kapunda, South Australia) were incubated at 38 ° C. for 3 days. After 3 days, the embryos are crushed and removed from the eggs, which are made of plastic tubes (for eggs to be stretched and suspended in the plastic film at the top). In a hammock). DMEM (2 mL) containing penicillin and streptomycin was added to each cup before adding the eggs. The top Petri dish was kept sterile. Incubation was continued in a humidified 37 ° C. incubator.

  On day 4, chorioallantoic membrane (CAM) began to grow and a photograph of each embryo was taken at x5 and the image of CAM was analyzed using image analysis software (Video Pro 32, Leading Edge Pty Ltd, South Australia). The area was measured. The embryos are then grouped according to their CAM area, which have a control embryo in each for comparison. There were 4 balanced embryos when treated with 6.25, 12.5 and 25 ng of homoharringtonine. Grouping is important because changes in these early developmental stages during the growth of the CAM are dramatic. The relatively small size difference on day 4 translates into a large difference in CAM on day 5, which makes it difficult to compare treatments. The material was used in a methylcellulose disc, which was first dried overnight under vacuum. The methylcellulose disc is applied to the top of the CAM and at the beginning of the treatment it is at least 3-4 times larger than the CAM area, which means that the treatment has spread over the entire CAM surface.

  On day 5, skim milk with contrast agent was injected into CAM. The photos were then taken at various levels of magnification up to x63x. Quantitative measurements were made from x5 photographs. CAM area and vein and artery length were measured using image analysis (Video Pro 32, Leading Edge Pty Ltd, South Australia). Subsequently, the relative value of the length of the blood vessel was calculated as the total length / CAM area. Statistical analysis was performed using SigmaStat and OneWay ANOVA with p <0.05 as the level of significance.

  FIG. 3A illustrates that the normal organization of the CAM is uniform, the main vein drains in the left direction, and the arterial branch extends to the top and bottom edges of the CAM To do. FIGS. 3B and 3C graphically illustrate the tracing of venous and arterial branching, as performed for measuring vessel length.

The angiogenesis inhibitor homohaligtonin was obtained from ChemGenex Therapeutics, Inc. (Menlo Park, Calif.) And was prepared to the appropriate concentration in sterile water. The initial dose with homoharringtonine caused embryo death because the dose decreased. Homoharringtonine was used at doses of 6.25, 12.5, and 25 ng (11.3, 22.5, and 45 nM) and these were compared to the water treatment controls. The results are shown in Table 2. Homoharringtonine reduced the proliferation of the CAM to 42% of the control in the case of CAM treated with 25 ng. The venous, arterial, and total vessel lengths were also significantly reduced for the 25 ng group, and vessel lengths were significantly reduced for the 6.25 and 12.5 ng treated groups I did not. The venous, arterial, and total blood vessel lengths were reduced to 15%, 18%, and 17% of controls, respectively. Not surprisingly, for all three dose levels of homoharringtonine, the relative arterial length is significantly reduced, the relative vessel length is also reduced, and the highest dose of homologous Only in the case of Hallingtonin, the relative vein length and total vessel length differed significantly.

  CAM homoharringtonine treatment resulted in a significant reduction in blood vessels, as illustrated in FIG.

  As shown in FIG. 4, even with the lowest dose of homoharignonin, the CAM is smaller and normal vascular organization is impeded. Note the overlap of large veins and arterial branches at the bottom of the CAM. The CAM at 12.5 ng had a general reduction in blood vessels and there were not many obstacles in organization. The highest dose of 25 ng left only fine trace blood vessels and the development of blood vessels was almost completely blocked. A 25 ng dose killed one smaller embryo.

  The changes seen due to homoharringtonine at higher magnification were specific and did not resemble other substrates tested. In FIG. 5, a normal CAM and a 25 ng homoharringtonine treated CAM are shown. Water control is well visualized. Homoharringtonine treatment results in a significant reduction in blood flow, and there are only a few fine blood vessels in the area where red blood cells are delivered. A unique feature is a black spot that spreads in the visual field showing red blood cells trapped in blood vessels where blood flow has stopped. This is compared to the changes seen when using taxol and the diffusive leakage of red blood cells out of the skeleton of larger vessels without the blood vessels and residual blood flow.

  The anti-angiogenic activity of homoharringtonine was tested using early chicken chorioallantoic membrane (CAM). The use of homoharringtonine results in a significant reduction in blood vessel development during CAM, with differences in both the potency and qualitative changes observed from Taxol. These differences can be reflected in changes in the mechanism of action, such as proliferation of affected endothelial cells, apoptosis, and migration due to these substrates.

FIG. 1 shows the general chemical structure of the cephalotaxin family. FIG. 2 is a drawing showing the chemical structure of homoharringtonine. FIG. 3 shows a chorioallantoic membrane (CAM) blood vessel. FIG. 3B is a diagram showing veins in the CAM. FIG. 3C is a drawing showing veins and arteries in the CAM. FIG. 4 is a drawing showing the influence of homoharringtonine in CAM. FIG. 5 shows a comparison of qualitative changes caused by homoharringtonine and taxol.

Claims (22)

  A medical device comprising a device body and a coating on a surface of the device body, wherein the coating comprises cephalotaxin.   The medical device of claim 1, wherein the medical device is other than a stent.   The device is a catheter, endoscope, wound healing bandage, tissue / organ barrier, suture material, artificial organ, artificial organoid, implantable monitor, defibrillator, pacemaker, implantable pump, cell reservoir, prosthetic device, and The medical device of claim 1, selected from the group consisting of a shaping device. A medical device comprising a stent and a coating on the surface of the stent containing cephalotaxin,
The medical device, wherein the device does not have another single coating on the stent containing heparin.   The medical device according to claim 1, wherein the coating further comprises a polymer.   The medical device of claim 5, wherein the polymer comprises a biopolymer.   The medical of claim 6, wherein the biopolymer is selected from the group consisting of collagen, fibrinogen, hyaluronic acid, lipid complex, chitin, albumin cyclodextrin, glucosamine, carbohydrate complex, polylactide, polyglycolide, and copolymer. device.   The medical device of claim 5, wherein the polymer comprises a synthetic polymer. The medical device according to claim 8, wherein the synthetic polymer is selected from the group consisting of Dacron, nylon, polyurethane, Lycra ^{(registered trademark)} , Gore-Tex ^{(registered trademark)} , polyethylene, polystyrene, polypropylene, polycarbonate, and polyethylene glycol.   The medical device according to claim 1, wherein the coating further comprises a non-polymeric material.   Cephalotaxin according to any of claims 1 or 4, wherein the cephalotaxin comprises homoharringtonine (cephalotaxin, 4-methyl-2-hydroxy-2- (4-hydroxy-4-methylpentyl) butanedioic acid ester). Medical device. The cephalotaxin has the formula:

[Where:
R ₁ is an ester or substituted alkyl, and R ₂ is an ester or substituted alkyl]
The medical device in any one of Claim 1 or 4 containing the compound shown by these.   The medical device according to claim 1, wherein the device further comprises a second coating.   The medical device according to claim 1, wherein the medical device comprises two or more coatings.   The medical device according to any of claims 1 or 4, wherein the coating further comprises a second drug.   A medical device comprising a matrix and a cephalotaxin contained in the matrix.   The medical device of claim 16, wherein the matrix is biodegradable.   The medical device of claim 16, wherein the matrix is a timed release matrix.   A method comprising contacting a host in vivo with a medical device according to any one of claims 1, 4 or 16, wherein the device is in an amount sufficient to inhibit angiogenesis. The method comprising providing cephalotaxin.   A method for treating an angiogenic disease comprising contacting a host in vivo with a medical device according to any one of claims 1, 4 or 16, wherein the device is an angiogenic disease Providing a sufficient amount of the cephalotaxin to inhibit the onset or progression of.   21. A method according to any of claims 19 or 20, wherein the contacting step comprises implanting the medical device in the host.   A delivery device comprising a catheter having a cavity and the device of claim 4 contained in the cavity.

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